Host Immune Signatures as Therapy Response Biomarkers in Metastatic Renal Cell Carcinoma
Abstract
This project is focused on developing biomarkers that can predict responses to therapies for patients with aggressive kidney cancer. Kidney cancer has an annual incidence of ~64,000, and accounts for ~14,000 deaths per year in the United States. The prognosis for this disease has historically been poor. Targeted therapy against the Vascular Endothelial Growth Factor or its Receptors, and most recently the immune checkpoint inhibitors (a type of immunotherapy), have changed the prognosis of patients with metastatic kidney cancer, which is the most aggressive form of kidney cancer. The efficacy of each therapy varies tremendously among patients and frequently resistance can develop. Some targeted therapies can significantly influence the complexity of immune factors in tumor microenvironments, thus potentially affecting the efficacy of immunotherapy. Therefore, it is critical to develop predictive markers of response for better therapeutic designs. Tumor genetics is absolutely a crucial factor in the treatment response. However, the host immune system plays a crucial role in recognizing and combating tumors. We think that differences between host immune defense systems may significantly influence responses or non-responses to targeted therapies or immunotherapy. T and B cell receptors (TCR/BCR) are key players in tumor antigen recognition. Multiple studies have shown that various targeted therapies can promote a more active anti-cancer immune environment by enhancing the adoptive immunity. Additional studies have shown immunotherapy increases in the size and diversity of the immune cell repertoire. We have recently developed several novel computational approaches to extract the sequence information of the immune cell repertoire from the existing genome data sets. With these approaches, we found a positive association between tumor mutation load and the local immune cell repertoire diversity. We hypothesize that response to targeted therapy and immunotherapy can be reflected in the dynamics of immune repertoires as well as in the gene expression signatures of white blood cells. We think that the signatures of host defense systems potentially serve as predictive biomarkers of therapy response. We propose to identify and characterize the differences of the immune cells between kidney patients who do and do not respond to targeted drug therapies or immunotherapy. The proposal combines bioinformatics, molecular genetics, and clinical science to define signatures of the host immune system in the course of kidney cancer progression and treatment resistance. The success of this study will identify novel strategies (for example, when combining targeted therapy and checkpoint blockers) to improve treatment plans in kidney cancer, and potentially other cancers. In addition to potential use as predictive biomarkers of drug sensitivity, the findings of the proposed study may serve as new targets for drug discovery.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910551
Entities
People
- Toni K Choueiri
Organizations
- Dana–Farber Cancer Institute
- United States Army